Project Summary Tissue loss due to trauma, disease or congenital abnormalities remains an intractable clinical challenge. There are profound deficits in how humans heal and recover from tissue damage and few innovations in regenerative medicine have reached the clinic or improved standard of care. Formation of dysfunctional scar tissue remains the default pathway for repair in the body. The immune system is the first responder to trauma yet this response, and its capacity to orchestrate tissue repair, has been largely ignored. Engineering tissues generally involves combining cells and biomaterial scaffolds with a suite of biological cues to stimulate new tissue development. Until now, these tissue engineering tools have been designed to target stem cells, vascular development, or tissue morphogenesis. Here, we are shifting the focus of tissue engineering design towards direct therapeutic manipulation of the immune system. The remarkable success of cancer immunotherapies highlights how the adaptive immune system is amenable to exquisitely robust intervention and the potential for regenerative immunotherapies. We introduce the concept of regenerative immunotherapies that engage and manipulate the effector class of T cells. Emerging understanding of tissue specific immunity, the role of senescent cells in tissue trauma and repair responses will be combined with our new and unexpected findings on pro-regenerative T cells. Single cell genomic analysis of immune subsets, stromal, and senescent cells combined with novel computational algorithms will be used to develop tissue- specific senescent and immune networks in homeostasis, aging, trauma, and disease. This foundation will serve as the basis for cell and molecular therapy design to enhance T cell mediated pro-regenerative immune responses. While broadly applicable to many tissues, we will first apply regenerative immunotherapies to musculoskeletal tissues before extending to additional tissues. Collectively, these studies will transform traditional thinking of the immune system by re-imagining the immune system as the body?s repair system and use this platform to engineer regeneration.